Control of Neural Development and Function by Glial Neuroligins Sakers and Eroglu 165

Control of Neural Development and Function by Glial Neuroligins Sakers and Eroglu 165

Available online at www.sciencedirect.com ScienceDirect Control of neural development and function by glial neuroligins 1 1,2,3,4 Kristina Sakers and Cagla Eroglu Neuroligins are a family of cell adhesion molecules, which are close neuron-neuron contacts form the basic functional best known for their functions as postsynaptic components of unit of the nervous system. Formation of these synaptic the trans-synaptic neurexin–neuroligin complexes. Neuroligins structures is thought to be controlled by homophilic and are highly conserved across evolution with important roles in heterophilic transcellular interactions between a num- the formation, maturation and function of synaptic structures. ber of cell adhesion proteins (reviewed in Refs. [1–3]) Mutations in the genes that encode for neuroligins have been that adhere specific axons to their proper postsynaptic linked to a number of neurodevelopmental disorders such as partners. These trans-synaptic cell adhesion molecule autism and schizophrenia, which stem from synaptic (CAM) complexes ultimately recruit neurotransmitter pathologies. Owing to their essential functions in regulating receptors necessary for synaptic communication. synaptic connectivity and their link to synaptic dysfunction in disease, previous studies on neuroligins have focused on The neuroligin (NL) family of CAMs are composed of five neurons. Yet a recent work reveals that neuroligins are also members in humans, four homologs of which are present in expressed in the central nervous system by glial cells, such as mice [4]. Over the past three decades, NLs have been astrocytes and oligodendrocytes, and perform important roles extensively studied for their roles in regulating synaptogen- in controlling synaptic connectivity in a non-cell autonomous esis and synaptic function. Thus far, an overwhelming manner. In this review, we will highlight these recent findings majority of these studies regarded NLs primarily as neuronal demonstrating the important roles of glial neuroligins in post-synaptic proteins [5,6]. The functions of postsynaptic regulating the development and connectivity of healthy and NLs are accomplished by the trans-synaptic interactions diseased brains. with presynaptic neurexins (NRXs) [7] (Figure 1a). A com- plex recognition code between different neuroligin and Addresses neurexin isoforms and splice variants exists, which is thought 1 Department of Cell Biology, Duke University Medical Center, Durham, to provide synapse subtype specific recognition between NC 27710, United States 2 axons and dendrites [8–10]. While loss of a single NL is not Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, United States lethal in mice, global ablation of NLs1–3 results in perinatal 3 Duke Institute for Brain Sciences (DIBS), Durham, NC 27710, United death [6], underscoring the importance of these proteins in States 4 development. The emphasis of NLs in CNS development Regeneration Next Initiative, Duke University, Durham, NC 27710, and function is further signified as mutations in both NL3 United States and NL4 are associated with Autism Spectrum Disorders Corresponding author: Eroglu, Cagla ([email protected]) (ASD) [11,12], in which synaptic dysfunction is thought to underlie the complex social and cognitive pathologies. Current Opinion in Neurobiology 2019, 57:163–170 Numerous recent studies, investigating gene expression This review comes from a themed issue on Molecular neuroscience in different CNS cell types, demonstrated that NLs are Edited by Yishi Jin and Tim Ryan expressed in multiple glial cells, particularly astrocytes and oligodendrocytes, with cell-intrinsic and extrinsic functions. In this review, we will focus on three NLs (NLs1–3), which have been well studied in rodents and humans and we will highlight studies demonstrating: 1) https://doi.org/10.1016/j.conb.2019.03.007 the sufficiency of glial NLs to mediate neuronal contacts 0959-4388/ã 2018 Elsevier Inc. All rights reserved. via NRXs, 2) the functional roles of glial neuroligins in glial development and synaptic connectivity, and 3) how glial NLs participate in the pathophysiology of diseases such as glioma and neurodevelopmental disorders. Introduction Neuroligin family proteins are expressed in Classically, synapses in the brain are defined as apposi- glial cells tion of two neuronal elements; a pre-synaptic bouton Heterologous connections can be formed between neu- from an axon and a post-synaptic density that is local- rons and non-neuronal cells that express NLs [7,13,14]. ized to a dendrite. Neurotransmitter release-mediated Exogenous expression of NLs in fibroblast-like cells, such communication (i.e. synaptic transmission) at these as HEK293T or COS7, is sufficient to attract axonal www.sciencedirect.com Current Opinion in Neurobiology 2019, 57:163–170 164 Molecular neuroscience Figure 1 (a) Neuroligin (b) (c) Neurexin dendrite Ca2+ channel AMPAR NMDAR axon astrocyte NL2 cKO (d) (e) NL2 CTRL NL2 cKO L1 L2/3 L4 L5 L6 P1 P7 P21 P21 Synaptogenesis Current Opinion in Neurobiology Astrocytic NL2 controls astrocyte morphogenesis. (a) Schematic of neuroligin–neurexin interactions at the synapse. Pre-synaptic a-neurexins and b-neurexins interact with postsynaptic neuroligins to recruit receptors to the post-synaptic density and calcium channels and synaptic vesicles to the active zone. (b) Electron micrograph depicting an astrocyte (cyan) contacting both a dendrite (red) and an axon (green) at the synapse. (c) 3D reconstruction of b. (d) Schematic of postnatal mouse astrocyte development. From P7 to P21 astrocyte territories rapidly increase in size and infiltrate the neuropil, coincident with synaptogenesis. With loss of astrocytic NL2 (cKO) astrocytes are smaller and less complex, with decreased loxP/+ loxP/loxP ability to infiltrate the neuropil. (e) Max projections of confocal z-stacks of medial prefrontal cortical astrocytes at P21. NL2 or , both carrying a floxed Rosa-TdTomato allele, were postnatally injected with Cre plasmid to produce sparse CTRL or cKO astrocytes, respectively. Scale bar = 25 mm. Images from 1b–c are courtesy of Dr W. Chris Risher, Marshall University. contacts and cluster presynaptic proteins at the heterolo- lifetime of the animals [25 ,26] suggesting long-term gous connection via transcellular interactions with axonal involvement in maintaining astrocyte-neuron interactions NRXs [7,14]. However, until recently, the endogenous and astrocytic function. Recently, these data were cor- expression of NLs in non-neuronal cells was largely roborated in astrocytes via in situ hybridization of NL ignored. Moreover, astrocytic NL expression may be lost mRNA in the mouse cortex, and by RT-PCR and western during long-term culturing in serum-containing media, blotting for NL mRNA and protein, respectively, in which is well-known to cause astrocytes to lose their in isolated astrocytes from rat brains [27 ]. Together, these vivo gene expression profile [15]. There were several findings provide strong evidence for NL expression in studies, however, that investigated NL expression in CNS glia. the CNS and have revealed the presence of NLs in cultured Schwann cells in vitro and in vivo, in astrocytes Glial neuroligins control neural development in the spinal cord and retina, as well as in oligodendro- via transcellular interactions with neurexins cytes and NG2+ oligodendrocyte progenitor cells [16–18]. Neuronal NLs are well studied for their functions in controlling formation of synapses [5,7] and synaptic In the last decade, decreasing sequencing costs and strength [6,28]. These functions of NLs are dependent improved cell purification methods have enabled large on their ability to transcellularly interact with NRXs efforts to characterize cell-type specific transcriptomes in (Figure 1a). In contrast, through interactions mediated the CNS. These datasets are comprised of FACS sorting by their intracellular C-terminal domain, NLs recruit or cell-specific ribosome purification [19–21], and single actin remodeling proteins to control dendritic arboriza- cell analyses [22,23] of brain cells, as well as acutely tions and stabilize postsynaptic structures [5,29,30]. In purified human astrocytes [24]. Mining of these datasets rodent neurons, NL1 directly interacts with Rho-GTPase reveals that NLs1–3 are expressed in astrocytes and activating proteins (GAPs) to ultimately stimulate assem- oligodendrocytes to an equivalent or higher level com- bly of F-actin and activation of this signaling pathway pared to neurons [20,24]. In astrocytes specifically, NL results in increased spine density, synaptogenesis, and transcripts maintain constant expression throughout the enhancement of long-term potentiation in the Current Opinion in Neurobiology 2019, 57:163–170 www.sciencedirect.com Control of neural development and function by glial neuroligins Sakers and Eroglu 165 hippocampus [31]. Moreover, NLs are sufficient to recruit Neuroligin–Neurexin adhesions control myelin-axon Wave Regulatory Complex (WRC) proteins to the cell contacts membrane to stimulate F-actin assembly, synaptic bou- Oligodendrocytes are highly complex glial cells that ton growth and synaptic transmission [32,33 ]. myelinate axons in the CNS. Multiple oligodendrocyte processes contact nearby neuronal axons, where they CNS glia are highly polarized cells, with many branches tightly wrap newly synthesized myelin around. Proctor extending to contact neurons, synapses, and blood ves- et al., using cultured oligodendrocytes and neurons, found sels. These

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